Leukemia and preleukemia are phenotypically characterized as having a block in differentiation. This block provides the abnormal cells of the patients with a growth advantage over the normal hematopoietic cells. In addition, patients with preleukemia and leukemia die from infection and hemorrhage because they have decreased number of mature blood cells as a result of inability of the abnormal cells to differentiate correctly. Recently investigators showed a role for all trans-retinoic acid in treatment of acute promyelocytic leukemias. We and others have shown that 1,25 dihydroxyvitamin D, {1,25(OH)2D3} can induce blast cells from leukemic lines and patients to differentiate terminally to macrophage-like cells; in contrast 1,25(OH)2D3 slightly stimulated normal myeloid stem cells. A small clinical trial of 1,25(OH)2D3 for preleukemics conducted by us was hampered by their development of hypercalcemia (major side-effect of vitamin D3 compounds). We initiated a NCCP-funded study to identify vitamin D analogs that induced differentiation and inhibited proliferation of leukemic cells without causing hypercalcemia. To date, over 175 novel vitamin D analogs have been examined and 21 fulfill our goals. 1,25(OH)2- 16ene-23yne-D3 was particularly exciting because it was able to cause a significant lengthening of survival of leukemic mice with little toxicity. We will continue to design and synthesize (see Okamura's proposal) novel vitamin D analogs that potently induce differentiation and inhibit proliferation of leukemic cells from both cell lines (Specific Aim 1), and patients (Specific Aim 2), without inhibiting proliferation of normal hematopoietic progenitor cells (Specific Aim 3) and without causing hypercalcemia (see Norman/Henry proposal). In addition, these novel analogs should significantly increase survival of leukemic mice (Specific Aim 4) and decrease number of human leukemia cells in SCID mice (Specific Aim 4). Our most interesting vitamin D analog [1,25(OH)216ene-23yne-D3] will be tested for toxicity and efficacy in preleukemic patients (Specific Aim 5). Taken together, this proposal in concert with the other two, should develop novel vitamin D analogs that may help in the treatment of preleukemia nd possibly a wide-range of other cancers and precancers.